Surfactant protein B deficiency due to rare, homozygous, loss of function mutations in the surfactant protein 5 gene (SFTPB) invariably causes lethal, neonatal respiratory distress syndrome. Non lethal genetic variants do not account for all changes in expression of surfactant protein B peptides in symptomatic infants. Disruption of SFTPB expression may also be caused by genetic variants in the surfactant protein C gene SFTPC). Human and murine studies have demonstrated tight linkage between the biosynthetic itineraries, post-translational processing, and functions in the pulmonary surfactant of surfactant proteins B and C. vlisfolded or mistargeted surfactant protein C peptides encoded by dominant negative mutations trigger the unfolded protein response in type 2 pneumocytes by formation of intracellular aggregates and/or retention in the endoplasmic reticulum, disrupt intracellular trafficking of the pulmonary surfactant, and interrupt surfactant protein B secretion. To determine the contribution of genetic variation in SFTPC to risk of surfactant protein B deficiency, we will test the hypothesis that gene - gene interactions between SFTPB and SFTPC increase risk of neonatal respiratory distress. To avoid extrapolation from small patient groups that may exaggerate or underestimate frequency estimates of rare genetic variants due to ethnic stratification, environmental selection, or genotype-phenotype heterogeneity, we have designed descriptive and case-control studies of symptomatic and asymptomatic infants that will provide sufficient statistical Dower (0.8) to identify combinations of variants and haplotypes in SFTPB and SFTPC associated with neonatal respiratory distress syndrome. Specifically, in the descriptive study, using high throughput automated sequencing of SFTPB and SFTPC and linked vital statistics-based phenotype data, we will determine associations between genotypes or haplotypes and neonatal respiratory distress in an unselected, de-identified, population-based cohort of Missouri infants (N=1,116). In the case-control study (N=480), using automated sequencing of SFTPB and SFTPC and both clinical and biochemical phenotype data, we will determine whether gene-gene interactions reduce or alter surfactant protein B expression. These studies will suggest new strategies for diagnosis and treatment of neonatal respiratory distress syndrome to improve infant outcomes. Neonatal respiratory distress syndrome is a major cause of infant mortality. Using state of the art methods for analyzing genetic code, we will determine whether interactions between 2 genes predispose infants to respiratory distress. These studies will suggest new strategies for diagnosis, treatment, and prevention of neonatal respiratory distress.